Journal of the National Cancer

Institute, Volume 62(5), P1295-

1317, 1317, May 1979 .

In the Middle: 1954-63-Historical Note t2 . z

Michael B . Shlmkin, M.D . 4

THE

SETTING

decade

This essay deals with the decade 1954-63 and thus

overlaps the earlier history of 1937-57 (1) . Its title
derives from two facts : It was the midperiod of the
history of the National Cancer Institute (NCI), and it
was the position I occupied in the hierarchy arid the
program .
My return from the disbanded Laboratory of Experimental Oncology in San Francisco (2) in 1954 was
traumatic for me and my family . There was a taste of
failure for me and a dislocation from what we considered the place to sink our roots . We rented a house
on the outskirts of Rockville, Maryland, a house
already occupied by two other refugees from the San
Francisco contingent . The family gradually adjusted to
the new environment, and I reported to the Director of
NCI, Dr . John R . Heller .
The headquarters of NCI in 1954 were in building
T-6, a temporary barracks-like structure that had been
occupied by the Public Health Service (PHS) during
World War 11 . Dr . Heller's office was at one end of the
second floor, and the activities assigned to his office
were in the rear wings . These activities included
Cancer Control headed by Dr . Raymond F. Kaiser, in
addition to statisticians, epidemiologists, science
writers, and administrative factotums grouped under
Research Services, with a commissioned officer in loose
charge. The Intramural Program, which now included
the rapidly expanding clinical branches, was headed by
Dr . G . Burroughs Mider . The grant area, representing
70% of the appropriation of $20 million that year, was
under the close supervision of Dr . Ralph G . Meader .
Heller, a considerate gentleman always, had explored
my reassignment on his last trip to my laboratory in
San Francisco . I was given the option to remain in San
Francisco on individual assignment Without support
other than my salary and with a courtesy faculty
appointment at the medical school, the prospects were
not attractive . The alternative option was to return to
NCI to some unspecified position 'commensurate with
my rank apd experience ." I dared to hope that such
a position would include clinical and laboratory
responsibilities, but apparently I was not acceptable in
these areas . Instead, I was asked to head the Research Services area because the incumbent had to be
retired for personal reasons .
The position was a make-work job, and an adminis-

trative staff assignment at that . I asked Heller for time

to get acquainted and to settle down a bit . It is
surprising how far the Pacific C-oast is from the centers
of activities in biomedical research on the eastern sea-

hu.trd and how soon one ccm Inse touch . \fy old
asxxiates at NCI had not ch :mRrd rnuch and were
pursuing the same JctlvlnC9 .lnd the s:nne vrndcuas as

http://legacy.library.ucsf.edu/tid/urc71d00/pdf

before . Mider was having . problems with the

laboratory chiefs, especially in pathology, and with the
executive officer of the NCI . The latter, filling what he
considered to be the vacuum left by the Director, was
attempting to guide program developments as well as
doing his job of fiscal and administrative management . The disagreements between him and the Associate Director in Charge of Research were obvious and
open . Mider wanted no part of ine, since he had
typified me as one who "runs with the fox and hunts
with the hound ." He wanted simple yes-or-no answers,
preferably in agreement with his . My approach always
has been to try to consider alternatives, which particularly in research are multiple .
The grant area interested me not at all . Moreover,
Meader made every decision and was constitutionally
unable to delegate any of his authority . Cancer control,
as it was being practiced and stringently constrained,
was not mY cup of tea . That left Research Services .
I soon found that the statisticians, who occupied one
large room in the back, were considered part of
Research Services . They were to assist Dr . Harold Dorn
in his demographic survey of cancer in the United .
States and to write statistical papers for the Director .
Dorn, however, moved to the National Institutes of
Health (NIH) level, leaving a talented group that he
had gathered without any visible plans for future
activities . A number of commissioned officers were also
attached to the epidemiology area, and thus by attribution became epidemiologists . The head man was Dr .
Alexander Gilliam, a welltrained professional with
tutelage under Dr . Wade Hampton Fro'st and assignments in poliomyelitis . Unfortunately, Gilliam (3) was
more concerned with methodology than with investigations and could find many reasons for not bestirring
himself in new departures . His associates reflected the
slow pace and detached approach of their leader . They
did complete some careful studies of cancer mortality
among minorities (4-6) and of leukemia (7), but at an
excruciatingly slow pace . I realized that the goodhearted Heller had a restand-rehabilitation center for

' Received May 19, 1978 ; accepted October SI, 1978 .

' Supported by Public tiealth Service contract NIH 26]-76-C-0919
from the National Cancer Institute .
.
s Part of a series of essays published in JNCI beginning with "As
Memory Serves-An Informal History of the National Cancer
tnstitwe, 1937-57" (J Natl Gincer Inst (suppl) 59 :559-rAQ 1977) . A
second essay . "t-ost Colony : taboratory of Expaimenral Oncology,
Srn Franrisco, 1947-54 : Historical Nose.' appeased in a later issue (J
Natl Cancer Inst 60479-188, 1978) . A fourth essay, 'A View From
Owside : 1963-75," is sdredulyd for puhlicaiion in the near future .
' Drpnnmrm uf tinnmumty Mrdicrnr Srhoul of Medicrne . Cni
.rnnv of (slifurnta ai San Diego . ta Jolla . CaliL 92095 .

1295

JNO . YOL . 62, NO. S, MAY 1979

1296 Shimkln
officers r .ho had not met their mark in previous
assignments or had carious personal problems . I also
became painfully suspicious that 1was being considcred in the same category .

Sonic events at this time complic :ned my reacfjustments . I was scheduled to give a paper on the San
Francisco clinical experiences in cancer chemotherapy
at the International Cancer Congress in Sao Paulo,
Brazil (8) . 1 was going to fulfill the chore as a matter of
pride . I was also scheduled to participate in the
Gordon Conference, an excellent way of becoming
reacquainted with cancer research and its leading
figures .
I proposed to Heller the creation of a branch of
biometry and epidemiology, for which I submitted a
research plan . This was accepted, though the branch
remained in the Office of the Director rather than
becoming part of the research arm of NCf . In this
anomalous place of the table of organization I never
did participate in staff meetings or other activities of
the intramural program, and my reports were not
incorporated with other research activities . There were
good aspects of the arrangement, however . I went
directly to Heller for budgetary needs and had a free
hand with all matters, as far as one can reconcile
bureaucratic processes with freedom .
Little could be done with the insecure officers that
had accumulated under Gilliam . I redefined their
assignments and set a time schedule by which their
tasks were to be completed . Gilliam resented the
interference and pointed out more deficiencies in the
data and analytical methods . Finally, the pressure
resulted in his requesting transfer to Cancer Control,
and Heller acceded .
The statisticians had a completely different set of
personnel problems than the so-called epidemiologists .
Here was a group of brainy, active people restive under
their restraints . They needed assurance and opportunities to spread their wings . It came as a surprise to them
that they were to choose their own problems as well as
to provide consultative services and that they were to
write their own papers rather than prepare them for
others .
In the NIH environment, a doctorate was a requirement for acceptance to full membership on the staff,
and none of the statisticians had made this rite of
passage . Nathan Mantel, a mathentatician with a
baccalaureate degree, was consultant to scientists with
several doctorates to their names, and later Jerome
Cornfield became head of the biometry department at
Johns Hopkins without any degrees beyond the baccalaureate . But for several, arrangements were made at
the University of Pittsburgh School of Public Health
or at local universities to acquire further formal education . A half-dozen bona fide doctors of science thus
arose from the group . Even in teuospect, the main
yield of such training was formal acceptance and selfconfidence rather than additional expertise .
It should be remembered that during the 1950's,
statistics and epidemiology were not considered quite
legitimate scientific disciplines in the biomedical sci-

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ences . The low regard for epidemiology was evident

from the fact that pafxrs dealing with cancer statistics
and demography were not even listed in the index of
cancer research literature compiled in 1948 (9) . Among
the panels created tinder the Committee on Growth
(COG) to advise the American Cancer Society (ACS),
epidemiology appeared only during the last year (1956)
of its activities .
Statistics and epidemiology at NIH were usually
tucked under some service function of the Office of the
Director. This situation was resolved by the forceful
participation of biometry and epidemiology in experimental design, especially in clinical trials . Scoffers of
the "epidemiologic method" still remain among laboratory scientists despite numerous demonstrations of
the power of the approach . Of course, epidemiology
cannot stand alone but must be interdigitated with
measurements from the laboratory sciences . Such measurements, in turn, must be tested epidemiologically if
they are to be useful . This need for interdisciplinary
groupings became difficult to meet when the biochemistry or pathology laboratory chiefs would attempt to block assignment of biochemists or pathologists to activities beyond their control . When such
personnel were acquired, by epidemiology programs,
relationships became strained between activities that
should have been working together .
During 1954-56, the personnel in biometry and epidemiology numbered about 40, 25 of which were in
biometry . The main tasks included analysis of data on
the cancer survey of 1948-49 in ten metropolitan areas
of the United States . This was a repeat of a survey
conducted in 1937, the first informative compilation on
the incidence and distribution of cancer. Preliminary
statistics for each metropolitan area were published
between 1950 and 1952, but now a more thorough
analysis was prepared . It was eventually published in
1959 as Public Health Monograph No . 56 (10) . A
decade for publication seems excessively long even in
retrospect, but the final product was worth waiting for .
The statistical staff of NCI had two types of professionals, mathematical statisticians and analytical statisticians . As implied by these designations, the mathematical group was more concerned with basic methodology and the mathematics it involved, whereas the
latter dealt with actual analysis of data . Cornfield and
Mantel were the mathematical statisticians to whom
other statisticians went for help on methodology . They
provided some important approaches to the problems
of estimations of rates (11), analysis of retrospective
data (12), and assessment of risk (13) .
I encouraged the preparation of statistical papers
useful to the clinician and written at a level that a
naive clinician such as myself could understand . Some
noteworthy papers appeared-e .g ., Ederer's simple
method for determining standard errors of survival
rates (14) and Axtell's procedure for computing sur
vival rates (15) . In another attempt at simplification for
broader distribution, the staff compiled a monograph
entitled Extent of Cancer Illness in the United States,
which gave demographic data in the form of questions

In the Middle : NCI, 1954-63 1297

and answers (16) . This material was extended to a
Congressional printing of Cancer-A It'orld IYide
,Sfenace, and it was revised as Cancer Rates and Risks
in 1964 and 1976 (17, 18) .
The transfer of the epidemiology section to Cancer
Control in 1956 left me in charge of only the Biometry
Branch . There was funher attrition by the loss of
several professionsl-level statisticians to other institutes
of NIH to head their programs and by the assignment
of Dr . Marvin Schneiderman to the newly created
Cancer Chemotherapy National Service Center
(CCNSC) to lead clinical biometry . The transfer of
Schneiderman was a most desirable extension of biometry into a vital new program . The relationships with
CCNSC became eveo- more intimate when I was
designated its Assistant Chief for Clinical Activities, a
post that lacked real substance . More meaningful was
the creation, under CCNSC, of an end-results evaluation section, with Dr . Sidney J . Cutler as its head .
This deployment and organizational structure lasted
until 1960, when Dr . Kenneth M . Endicott was appointed Director of the NCI and instituted a series of
reorganizations . During the period )955-60, 1 occupied
three posts : Chief of the Biometry Branch, Assistant
Chief for Clinical Activities of CCNSC, and Scientific
Editor of the Journaf of the National Cancer Institute .
In addition, for 9-months I substituted as head of the
Office for International Activities of NIH, which
launched the PL-480 program in international health
research .
From these vantage points and by frequent consultations with Heller, Endicott, and the immediate staff of
the NIH Director, I had a close view of the overall
picture of NIH during its golden decade . With ample
budgets that included enough unencumbered funds
with which new progiams could not only be planned
but initiated without delay with a minimum of reviews, reports, and other interferences, and in an
environment of exciting challenges, it was easy to be
successful . And one of the successes, I believe, was the
eventual growth to full stature of the numerate sciences
(19) of biometry and epidemiology .
The developments are best described by the actual
research events that I have chosen as examples . Some have been presented briefly before and have been the
subjects of papers in the literature to which reference is
made .
TOBACCO AGAIN
If there is any summit of achievement in cancer risearch during the past several decades, it must be the
discovery, irrefutable proof, and obvious importance of
the fact that tobacco smoking causes lung cancer in
man and is associated with other severe hazards to
health . The elements in the discovery provide a paradigm as well as an example of rejection of scientific
benefits by society .
Suspicions that tobacco fumes are not healthful and
that human lungs were not intended to be tobacco
smoke filters go back several centuries . But tobacco was

one of the luuative crops from the New 11'orldt the

vcry existence of some of the colonies depended on the
tobacco leaf .
By 1950 a concern arose in England and the United
States about the steep rise in mortality from lung
cancer . Some of the increased mortality was related to
urban residence, and some clinicians, such as Dr . Ahon
Ochsner, were convinced that it was related to smoking . Three simultaneous papers related smoking to
lung cancer by the retrospective ease-control method .
Plans were made shortly thereafter to mount prospective studies in England and the United States . Doll and
Hill (20) conducted their inquiry on 60,000 British
physicians, and Hammond and Horn (21) of the ACS
involved 187,000 men for their investigation . At NCI,
Dorn planned to use the holders of insurance among
veterans of World War I but was delayed by restrictions
against sending questionnaires and having them
printed . The NCI statisticians, of course, were svell
aware of the investigations and problems of design and
interpretation they presented .
I became interested in the problem while still in San
Francisco and analyzed the literature as part of a
review article on experimental lung tumors (22) . My
interests extended even earlier, inasmuch as one of my
first research assignments in cancer was to test air dust
samples for carcinogenic activity . The data appeared
suggestive, and I considered that the results of the
prospective studies would pretty well cinch matters ;
this conclusion was added to the galley of the paper .
Early returns from the Hammond and Horn (21)
study were announced at a small meeting called by the
ACS, to which I was invited . The results, as well as
those of the British workers (20), showed an increased
mortality among smokers, proportionately most
marked for lung cancer but numerically most evident
for heart disease . Dr. Ernest L. Wynder by then also
reported that tobacco smoke condensates elicited cancer
on the skin of mice and thus gave further credence to
the epidemiologic evidence . I was convinced sufficiently to stop smoking .
Heller appointed me as the NCI member to a
scientific committee organized by the ACS ; also included were representatives of the National Heart
Institute and the American Heart Association . The
committee was organized following a meeting of the
ACS at Lake George, New York, at which the ACS
recommended more vigorous research and public health
action in the area of smoking and lung cancer .
The scientific committee on smoking and health
held a series of six 2-day nieetings, reviewed the data,
and prepared a short, definitive report (23) . Its conclusions did not equivocate : " . . .the smoking of tobacco,
particularly in the form of cigarettes, is an important
health hazard ." The report, accepted for publication in
Science, appeared in 1957 . It created no particular stir
and was not accepted as sufficiently convincing by
either the National Heart Institute or the American
Heart Association . I recall a conversation with the
Director of the National Heart Institute, who dismissed
the report with a flip remark . The NCf, however, was
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1298 Shlmkin
doing not much bt'ner . Heller gathered his laboratory
ehirfs and receiced more denials than support . Dr .
M- J . Shear, an expert on carcinogenesis, and Dr .
Harold L . Stewart, the head pathologist, refused to
recognize epidemiologic data that were not confirmed
in laboratory animals . Dr . Wilhelm C . Hueper thought
that occupational causes of lung cancer were of greater
importance and needed public health controls more
than a social habit that represented individual choice .
Even the epidemiologists, with Gilliam in the lead,
voiced more doubts (24, 25) . Thus no consensus of
scientific opinion was available for Heller to present to
his superiors .
It is easy to take recourse in paranoia when one
meets opposition . Why would respected, secure scientists such as Shear, Stewart, and Hueper oppose the
obvious fact that tobacco smoking caused lung cancer
in man? Years later, I attributed their stance to a
Kuhnian explanation (26), that their paradigm of cancer research simply did not encompass the epidemiologic method . Pathologic morphologists of the generation of Stewart and Hueper did not use quantitation ;
qualitative recognition of visual patterns was their
main stock in trade . Shear, one of the pioneers in
chemical carcinogenesis, never did apply quantitative
bioassay procedures to his research .
Whether the same explanations apply to the opposition to the tobacco-smoking facts by such giants as Dr .
C. C . Little and Dr . R . A . Fisher is conjectural . Little
preferred support of research by'private enterprise
tycoons rather than by the Government and could not
resist the blandishments offered by the tobacco interests . Fisher, along with Dr. Joseph Berkson, pointed
out that the epidemiologic data lacked rigorous biometric design and was unacceptable to him unless the
world of the real conformed with the world of theory .
The statistical group at NCI continued to add data
on the subject . A transfer of funds to the Bureau of the
Census allowed a systematic assessment of tobaccosmoking patterns in the United States, the first study of
the distribution of the habit in our population (27) . A
retrospective study of lung cancer in women sustained
the relationship to smoking (28) . Dorn's inquiry (29)
on 250,000 veterans fully substantiated the prospective
studies of Doll and Hill (20) and Hammond and Horn
(21). And a group of us, with Cornfield in the lead
both aipnabeticaity and inteiiectuaify, w ote a discus=
sion (30) of the evidence and the questions that remain
relevant ; this has found its way into several compendia
of papers on social problems .
Despite the lack of agreement at NCI, the Surgeon
General, at that time Dr. Leroy E . Burney (31), did
issue a statement on July 12, 1957, declaring : "The
Public Health Service feels the weight of the evidence
is increasingly pointing in one direction : that excessive
smoking is one of the causative factors in lung cancer ."
He then ordered a fuller account to be prepared for his
signature ; this task was assigned to Dr . Lewis Robbins,
newly appointed to cancer control activities in the
Bureau of State Services . Over 20 drafts were prepared
before the paper finally appeared in the November 28 .
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1959, issue of the Journal of the dmrrican hfrdical

Association (JAlIA) . The impact of the conclusion that
smoking is a principal factor in the increased incidence of lung cancer was practically nil, esfxci :dly as
an editorial in the December 12, 1959, issue of JAMA
(p . 2104), took the teeth out of the report by labeling it
as conjectural .
Research on lung cancer epidemiology continued . A
contract with the Veterans Follow-Up Unit allowed an
investigation of the relation of lung cancer to the 1918
influenza epidemic and to mustard gas exposure (32) .
Influenza was not related to subsequent development of
lung cancer but gas exposure was . The subject of
tobacco smoking and its health hazards moved to
higher political and social arenas, with the tobacco
industry doing well-supported battle for its interests
against unorganized, fractionated health interests . On
the ACS board were recalcitrant members from the
tobacco states, and they threatened secession at this
danger to the economy of their region . The Federal
agencies were also under attack from legislators representing states in which tobacco was an important
commodity .
I became only peripherally involved in some of the
machinations, having been invited to stay out of the
subsequent policy discussions . Senator Maureen Newberger took a personal interest in the matter, and I
became her informal advisor . Her administrative assistant, Mr . Michael Pertschuk, wrote a book for her,
entitled Smoke Screen . Tobacco and the Public YVefJare
(33) . Pertschuk's later assignment to the Senate Commerce Committee articulated with the labeling of
cigarettes as a health hazard and prohibition of advertising of cigarettes on television . I was referred to
several members of the House of Representatives for
their support . They listened sympathetically and then
painstakingly recounted to me the political facts of life .
Idaho had no interest in tobacco, for example, but
needed support from South Carolina on matters concerning potatoes, and politically, one enemy is not
worth ten friends.
On lecture tours, in which Heller tacitly encouraged
me to participate, I would lock horns with Little,
feeling like an unsuccessful David against this respected giant of cancer research . I gathered cigarette
advertisements that on lantern slides in living colors
were a commenYary on our mercantile advertisement
culture, kept some audiences amused, and produced no
effects other than amusement . I recall one such lecture
to a meeting of the Lost Chord, a society of laryngectomized individuals, where the air was thick with
tobacco smoke . When I decided to offer my collection
for publication, it was not allowed by my superiors .
Thus an alternate method of an authorless presentation
was devised (34).
~
The story of the Surgeon General's report of 1964,
carefully orchestrated for public impact, has been well
told by Breslow (35) . 1 was excluded from the deliberations because I was no longer open-minded on the
subject . However, my assistant, Dr . Herman Kraybill,
was appointed to be the staff director for the enterprise .

In the Middle : NCI, 1954-63 1299

T:raybill made a mistake in admitting to a reporter that
it was not quite a carte blanche issue, and for this
prejudicial revelation he was summarily fired . I was

the beneficiary in having his useful talents returned to

my activities.
BILHARZIAL CANCER
Epidemiology has to be opportunistic, as any science
must be that depends on source material beyond its
control . Such opportunities relate personal interests
and talents to situations and materials . One of the
great strengths of the pursuit of epidemiology at the
Federal level is ready access to central repositories of
records, such as those of the Bureau of the C.ensus, and
influential extensions to international sources . Epidemiology cannot be restricted to one country, especially
one as homogenized as the United States in regard to
habits, nutrition, and other environmental factors . The
true arena of epidemiology is indeed the whole world,
where unusual situations provide possible insights into
causes of cancer and other disease .
In San Francisco I became acquainted with Dr . Piero
Mustacchi, an emigrant from the Italian colony in
Egypt, who was an ACS research fellow . Conversations
between us strengthened our mutual interests in urinary bladder cancer in Egypt, which was described in
the literature as being associated with infestation by
the fluke Schistosoma haematobium .
Review of the literature showed many descriptions
by pathologists, going back to the late 19th century .
However, there were no studies of the relationship of
such infestation and bladder cancer in a populationin other words, an epidemiologic investigation . Also
lacking were any attempts to replicate the condition in
animals or to test the fluke for carcinogenic activity
under laboratory conditions .
On a trip, to see his parents in Egypt, Mustacchi
explored the possibilities of research in the area . He
identified a number of hospitals in which cooperation
was proffered, and the U .S . Naval Medical Research
Unit (NAMRU 3) represented a potential for laboratory
research . He also brought back some dried and frozen
schistosomes, which required special clearance for importation . This material was implanted subcutaneously
in mice and proved negative for the induction of
'sarcomas at the site of injection (36) .
Five years later, in 1956, when Mustacchi was fulfilling his military obligations in the PHS, his assignment to my activities was granted . After an intensive
exposure to statistics and epidemiologic methods, he
was dispatched to Egypt to develop further our interests in bilharzial cancer .

Our plans included exploration of son7e Egyptian

population that could be followed for S . haematobium

infestation and bladder cancer and the development of

laboratory models, preferably subhuman primates .

Realistically, these goals were unlikely; thus our immediate and minimum aim was a survey of hospitals
for the telation of the presence of S . haernatobium ova
in the urine and bladder cancer .

The search for a likely population in which a

prospective study could be developed was unsuccessful .
The laboratory extensions, despite the interests of Navy
medical authorities in 1Yashington, also were not
realized . We were told that yellow fever regulations
prohibited the importation of Sudanese monkeys into
Egypt, but it was also apparent that the pathologists at
the NAMRU station in Egypt were not enthusiastic
about being burdened with these endeavors .
Mustacchi had completed gathering of the data in
the American Mission Hospital in Tanta when Nasser
seized the Suez Canal, and a major international crisis
soon followed . All foreigners were ordered out of
Egypt, and Mustacchi assisted in the evacuation . He
landed in Italy, and it was unlikely that any further
work would be done in Egypt in the foreseeable future .
Our small investment was extended to a survey in
Ghana, another area of endemic S . haematobium
infestation where, presumably, no increase in bladder
cancer was observed . Mustacchi proceeded to Accra and
Kumasi in Ghana . Data from there also indicated that,
following correction for age distribution and degree of
infestation, there was a good relationship between
parasitic infestation and the frequency of bladder
cancer .
The final report, greatly improved by the statistical
talents of Mantel, appeared in 1958 (37) . Obviously,
this important environmental cause of cancer, afflicting over 50 million people in Africa, needed more

attention .

Mustacchi returned to private practice in San Francisco but continued his interests in cancer epidemiology and published contributions on the epidemiology
of leukemia and testicular tumors . I explored the
possibilities of mounting laboratory research on S . haematobium carcinogenesis and found a receptive ear at
the Southwest Foundation in San Antonio, Texas,
which had a primate colony. A contract proposal was
developed but could not be activated because of fiscal
restrictions . By the late 1960's, long after my departure
from NCI, Dr . Robert E . Kuntz and his coworkers (38)
at the Foundation did succeed in infecting primates
with S. haernatobium and reported in 1972 that two
invasive bladder cancers had been induced .
Scientific and humanitarian opportunities in this
area, now more obvious and important, are as distant
as ever from realization . They await the political and
economic stability in the Near East that continues to
be a possible fuse for a world conflagration .

CLINICAL CANCER DATA

The involvement of the biometry staff in the activities of the national chemotherapy program allowed
expansion of statistical application to clinical problems . The Clinical Center was too young to have a
backlog of clinical experience, and no relationships
had been developed with outside clinical centers for
such work . Also, Federal employees usually were not
welcome to delve into hospital records ; bugaboos of
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1300 Shlmkin
cnd by others made such arrangements most difficult .
Ry kecpinG our eves open, however, we would find
an occasional opportunity . Exploitation of such opporurnities del>cnded ufon the availability of medical
officers and statisticians to undertake the necessary
analyses . Such analyses, for us, demanded a return to
the original records .

During the 1950's, the surgical approach to cancer

reached its apogee in aggressiveness, without impressive evidence of additional therapeutic effectiveness .
Some clinicians and statisticians in Great Britain and
the United States began to question even such vaditional, hallowed procedures as the Halsted mastectomy .
Indeed, irrefutable figures were not available to settle
the issue between the radical en bloc operation and
some types of less extensive excision .
In 1959 two surgeons from Rockford, Illinois, published a modest report (39) that indicated identical
survival rates following radical and simple mastectomy . During World War II, the Rockford area was
deprived of surgeons who performed the radical operation, so a natural experiment in comparative therapy
had occurred . A telephone contact allowed us entry for
a reexamination of the data, and a young medical
officer, Dr . Max Koppel, and a statistician were dispatched to gather the data on a prearranged form .
Our elaborate report (40) on 448 women of Rockford
substantiated the conclusions of Smith and Meyer (39)
that the radical resection yielded no demonstrably
better survival than the more limited operations . Our
main conclusion, however, was that formal clinical
trials were mandatory for the resolution of the issue .
The report attracted considerable attention, mostly
derogatory . I gathered a file of letters from various
professional bodies, including the American College of
Surgeons, that were tightrope exercises in avoiding the
issue . Even a resolution of the National Advisory
Cancer Council, pushed through reluctantly by Dr .
1 . S . Ravdili, lay ignored .
Many intriguing rejoinders were offered as rebuttals .
One was that the radical operation needed better
trained surgeons and thus kept less well-trained ones
out of the field . On this basis, one sarcastic surgeon
predicted that the simpler operations would be tested
only when they would be reimbursed at higher rates
than the radical ones . Another rejoinder was that
surgery' was expected only to control local disease ; this
suggested an extrapolation to penile amputation for
syphilitic chancre (41) . The day of more objective
consideration of surgical dogma was still in the future .
Another analysis of clinical results was undertaken
following discussions at an ACS workshop on lung
cancer (42) . The issue was whether pneumonectomy
yielded better results than lohectomy . Ochsner, who
espoused pneumonectomy, and Dr . Richard Overholt,
who preferred the more limited resection, agreed to
have their clinical experiences analyzed . Cutler and his
associates proceeded to do so and concluded that the
less extensive procedures yielded survival rates that
were as good as, and perhaps better than, those
recorded after more extensive surgery . Ochsner changed
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his approach, and this field did not arouse the controversy evident in breast canuer surgery .
A third clinical foray, undertaken by Koppel and Dr .
John C. Bailar Ill, explored the rcLnionship of adenomatous polyps of the colon to cancer (43) . Sprau,
Ackerman, and Moyer (44) of Washington University
in St . Louis had cast serious doubt that polyps were a
premalignant stage of cancer . If indeed cancer did arise
from polyps, a population deprived of polyps should
have a lolver risk of colorectal cancer . We found such a
population among patients of the Lahey Clinic in
Boston, where the polypectomy patients had been
carefully followed, but not patients found free of
polyps . Over 4,000 polyp-free patients were traced ; 19
had developed colorectal cancer-very close to the 22
that were predicted on the basis of the age distribution .
The incidence of cancer among 307 patients who had
adenomatous polyps removed also was close to that of
the general population . Thus no clear relationship of
adenomatous polyps and cancer of the lower intestine
was found, and further doubt was cast on the adenomatous polyp as a cancer precursor . The important
point, however, was that removal of adenomatous
polyps did not reduce the risk to colorectal cancer and
thus could not be used as a definitive preventive
measure .

END RESULTS IN CANCER

One of the NCI's earliest forays, initiated by Dr .
Leonard A . Scheele before World War II, was a
collection of clinical records on patients with cancer
from some hospitals on the eastern seaboard . The
purpose was to provide a base of information regarding treatment and survival . Dr. James Hawkins (45)
did write a paper on breast cancer on the basis of these
records, which then disappeared . The NCI Tumor
Clinic in Baltimore issued no reports on the experience
there . I compiled and analyzed data on patients with
breast cancer and the leukemias and lymphomas in San
Francisco (41) ; this was probably one reason I headed
the epidemiology and biometry activities on my return
to NCI .
In 1955 when the CCNSC was launched, there was
no intramural data base on the effect of cancer on
survival and the influence of various treatment modalities on survival . Analysis of the second ten-city survey
of cancer incidence had not been completed, and in
any case it did not include data on survival . The best
single source of such information was the Connecticut
Tumor Registry. This enterprise was the oldest continuing population-based cancer registry in the world,
having been initiated in 1935 . It also was closely
related to NCI by professional and financial ties,
inasmuch as the personnel available in Connecticut
were not adequate to analyze the data . An important
report from Connecticut was prepared in 1955 under
the guidance of Cutler (46) . In addition to demographic data, it had complete survival results .
Tumor registries also existed in California and
Massachusetts as well as in many major hospitals .

In the Middle : NCI, 1954-63 1301

There was some uniformity in how the data were
g-nhered but no central collation .

Administration facilities and the Memorial Hospital in

New Yotk, were not among the participants .

In my capacity as Assistant Chief for Clinical Activities of CCnSC . I suggested to Endicott the desirability
of creating a clinical data base with which the eventual
outcomes of more formal clinical trials could be
compared . The suggestion lay in abeyance until such
an activity was deemed appropriate and when some
funds became unexpectedly available (47) . The statistical unit under Cutler went to work immediately . The
first steps involved agreements by telephone for a
meeting of representatives from established cancer registrics and the creation of an informal organization . A
definite goal of reporting the data at the 1956 National
Cancer Conference was-a useful stimulus ; travel money
and minimum support to enable registries to provide
data were the essential requirements that made it
feasible .
A series of reports on 66,000 cancer patients was
presented at the 1956 meeting (48), and these reports
were expanded to double that number in a more
leisurely publication later (49) . The data were derived
from three central State registries and seven hospitals
throughout the country . As usually happens in such
activities, two large potential sources, the Veterans

The activity required standardization of criteria,

definitions, and ieport forms so that they could be
validly combined, and this involved many meetings
and visits of the cooperating statisticians . The size of
the operation also required computerization, a new
field in which all had to acquire experience .
Data derived from the end-results program could
encompass only crude features but did allow more,
detailed examination of specific problems . The cancer
population that was included, of course, was not a
random sample and undoubtedly underrepresented
poorer areas and hospitals that served such areas . In
the 1950's, however, the program was a large step
forward in providing factual information about what
was being achieved with cancer patients . Most clinical
papers on the subject were considerably more unrepresentative because failures were seldom reported . As one
surgeon put it, there are ten deaths in the hospital for
every one in the literature .
By 1959, the end-results group also was allowed to
expand internationally so that results recorded in the
United States could be compared with those in Europe.
An organizational meeting was held in 1959, with

Frevar 1 .-Meeting of the Ad Hoc Group on International Cooperation in Evaluation of End Results at Domus Medicus, Copenhagen, Lknmark, October 5-6, 1959 . Front roup, IrJI to right : M . A . Schneiderman (U .S .A .), A . McKenaie (United Kingdom), A . Korpela (Finland),
H . E . Pogosianr (U .S.S.R .), S4 . P . D. Logan (United Kingdom), M . B. Shimkin (U .S .A .). W. Haensxd (U .S .A .) . Second roro, ttJl to right :
E . T . Kremontr (U .S .A .), N . Ringerte (Sweden), X . Cellc (France), B . Sorensen (Denmark), W . I . Lourie, Jr . (U .S .A .) . K . L-ockwood (Den
mark), K . Magnus (Norway), J . Leguarinais (France), N . N . Blokhin (U .S .S.R .), E. Pedersen (Korway), E . A . Saxin (Finland), J . Clemmesen
(Denmark) .

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01

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1302 Shlmkln
reprrsentalisrs of cancer registrics from Denmark . EngI :rnd, Franu, Norway, Firrl .urd ind ttre United States .
AGrecments among international viewpoints are difficult to achieve, but ttre coordinating work of Afr .
11'illiam Lourie and others resuhed in a meeting in
Norway in 1963, where the results were presented and
eventually published (50) . Further developments in this
area were aborted by funding restrictions for international activities .

LEUKEMIA AND SIMIAN VIRUS 40

Epidemiology was officially shifted to Cancer Control in 1957 where, with other activities, it was dying
on the vine before )he total transfer of Cancer Control
out of NIH . Some of the functions were transferred to
the biometry group, including responsibility for three
officers assigned to Berkeley, Pittsburgh, and Boston .
The Pittsburgh School of Public Health, especially
with Dr . Anthony Chiocco there, became a training
center for epidemiologists and statisticians not only for
\CI but also for NIH .
Another relationship that was stimulated was with
Dr. Alexander Langmuir's epidemiology program at
the Communicable Disease Center (CDC) in Atlanta .
Langmuir would give the 2-year medical officers fulfilling their service obligations a 6-week intensive
course and assign them to health departments for
working experience . Academicians considered such
training too quick and dirty, but there were too many
examples of effective performance by the young physicians to be ignored . A transfer of funds was made to
CDC to extend its interests beyond the classical infectious diseases into chronic disease epidemiology .
One payoff to the arrangement occurred in 1959,
when a physician in Chicago alerted CDC that in a
small suburb of Niles, Illinois, 7 cases of acute leukemia had occurred within 3 years . Langmuir dispatched one of his young officers, Dr . Clark Heath
(5l), for an investigation . NCI added an engineer to
monitor the area for environmental hazards, particularly radiation sources . An intensive survey of the area
led to no elucidation of the mini-epidemic, if indeed
this cluster of cases could be so termed . It did arouse
interest in identifying and studying other clusters of
neoplastic diseases, especially leukemia, and resulted in
some papers on the methodology of identifying timespace congruences (52) .
A related area of interest was leukemia in cattle,
which was a concern in Europe as well as the United
States . After depletion of its cattle by the Germans
during \1'orld War 11, Denmark had replenished its
herds by the use of semen from a prize bull, which
then developed leukemia . The problem was potentially
of tremendous economic importance . Bendixen (53)
devoted the resources at his Danish institute to the
studies and collaborated actively with veterinarians at
the Uni .ersity of Pennsylvania (54) .
Only after 1960, when an epizootiology section was
established under epidemiology, could NCI participate
actively in these problems . Dr . Richard J . Tjalma,
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recruited to head the activity, was stationed in Nfichigan in cnder to conduct survcys and epidemiologie
studies on cattle lymphoma . lie, with Dr . William A .
Priester and Dr . James Peters, also compiled a standard
nomenclature of veterinary pathology that is a landmark in the field (55) .
A frightening possibility of an iatrogenic induction
of cancer in man arose when Dr . Bernice E . Eddy
obtained sarcomas at the site of injection of simian
virus 90 (SV-40) into hamsters (56) . SV-40 was an
indigenous virus of monkeys from which kidneys were
obtained for the growth of poliomyelitis virus ; the
killed-type vaccine was prepared from this virus . Eddy
was on the staff of the Division of Biologics Control,
then under NIH, and she was a collaborator of Dr .
Sarah E . Stewart (57) in the polyoma work .
The news shuddered through the higher echelons of
NIH, which already had encountered too many problems with polio vaccines, and I was instructed by
Endicott to do something about it . I first talked with
the Director of Biologics Control, whose demeanor
clearly indicated that he would have preferred to be
elsewhere . Samples of the polio vaccine were still
available, and it had already been determined that
about half of the lots were contaminated with SV-90 .
The lots of vaccine used in the polio immunization
program were distributed by counties and an excellent
reconstruction was made of the geogrzphic areas where
such lots were used as well as the cohorts of children
who received the vaccines .
Further inquiry, which related the frequency of
leukemia and other neoplastic disease and all causes of
mortality to the virus-contaminated versus virus-free
vaccines, was conducted by Dr . Joseph F. Fraumeni, Jr .
(58). Everyone breathed a sign of relief when no
evidence could be reported, at least at 7 years following
the vaccinations, of increased cancer or other untoward
effects among the children who hacJ received SV-90contaminated vaccines .
Eddy was not exactly thanked for her research, and
neither she nor Stewart was ever adequately recognized
for her achievements . In fact, many times they were
not even believed until someone had repeated their
work and reviewed their pathology sections .

CANCERS CAUSED BY AFLATOXINS

In 1960 two parallel epidemics among animals
occurred . One was in England, where thousands of
chicks and ducklings were dying with acute liver
necrosis . The other was detected in the northwestern
United States, where rainbow trout were dying with
large, lumpy livers that turned out to be hepatocellular
carcinomas . No association was evident between these
outbreaks, which were eventually related to the contamination of food with aflatoxin .
I was summoned to Boise, Idaho, to attend a meeting
of fish raisers who were threatening to sue their fish
food producers, because a few telephone calls appeared
to relate cancers in the fish to food sources . The
situation was fanned by the veterinary pathologist who

In the Middle : NCI, 1954-63 1303

had made the original diagnoses and demanded imtant
action (50) .

The epidemiologic features of the fish disease involved a change in the method of raising the animals .
Before t1'orld War II, hatchlings were fed offal from
slaughter houses ; this unpleasant operation was terminated as soon as the fingerlings could be released into
streams . The food processing industry then devised
convenient pellets of fish meal with all necessary
constituents on which the fish thrived . Now the fish
could be kept in hatcheries until they reached adult
size and were released for ready and easy catch by the
fishermen .
Thal the occurrence of trout hepatoma was indeed
related to food sources was quickly verified . One large
company provided food pellets to which practically no
hepatomas could be traced ; another source was so
carcinogenic that it became known as the "hot diet ."
Hueper (60) immediately added his observations to
the problem, but it needed more intensive study not
only because of its scientific interest but because the
economic interests now involved legal and political
allies . Weekly memoranda on the developments, ordered by the Office of the Surgeon General, were
relayed through three layers of ambitious memorandum carriers .
The laboratory facilities at NIH were not adequate
for research on fish, and it seemed preferable to place
the endeavors in a center devoted to fish problems . The
Western Fish Nutrition Laboratory in the State of
Washington was chosen ; this activity of the Department of the Interior was headed by Dr . John Halver . A
transfer of funds enabled Halver to begin unraveling
the carcinogenic factor in food to which the fish were
exposed (61) .
The usual hepatocarcinogenic contaminants were
promptly ruled out, but in the process the rainbow
trout were found to be as susceptible as rats to
hepatomas fbllowing exposure to azo dyes, aminofluorene, and urethan . A metabolic chamber for fish,
which allowed collection of urine, was devised for
these studies . After more meetings and consultations, it
was decided that actual fractionation of carcinogenic
Food was required, and the primary hypothesis was
that polymerized fats were the culprits .
A parallel search of the literature and consultation
with fdod chemists indicated that the epidemic of
hepatonecrosis in English poultry w as traced to peanut
meal in the diet, the peanuts having been imported

from Africa and Brazil . There, under warm humid

conditions, the shells cracked and the nut became the
medium for the growth of a mold, Aspergillus /lavus .
Such contaminated peanut meal fed to rats produced

hepatomas (62) .
Two teams of chemists, one in England and one at
the Massachusetts Institute of Technology (MIT), raced
to identify the carcinogenic product of the mold,
'.ocalized to compounds that fluoresced blue and green
under ultraviolet light .
f:raybill (63), my special assistant with expertise in
food chemistry, arranged for a rapid -allocation of

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funds to the MIT group for their work on what by

now was termed aflalnxin . The relationship of aflatoxin and trout hepatomas became ever more obvious
when Halver reported that the carcinogenic fractinn of
the fish diet t.as in the newral fat rather than in the
precipitates . Dr. Gerald Wogan at MIT sent some
chemically pure aflatoxin to Halver, and Halver sent
some carcinogenic fish food samples to 11'ogan . The
correlation between the content of aflatoxin in the fish
diets and carcinogenicity in fish was perfect, and the
aflatoxin promptly induced hepatomas in trout . The
trout hepatomas in this investigation were the first
neoplasms to be produced by the defined chemicals .
The story of trout hepatoma seemed complete . The
ramifications of aflatoxin carcinogenesis in man were
now extended to field investigations in Africa and
Southeast Asia, where an excellent correlation was
found between the frequency of hepatoma and the aflatoxin content of food .
Aflatoxin is one of the more active carcinogens of
natural origin to which millions of people throughout
the world are exposed . It is one of the environmental
carcinogens whose level is reducible by modern food
technology .
MAMMOGRAPHY
Perhaps the most far-reaching and important application of biometric-epidemiologic methodology was
made in the field testing of X-ray .mammography as a
detection technique for breast cancer . This occurred in
1962, and the events have been recounted by several
participants .
The role of the biometry group follows . Dr : Lewis
Robbins, then in charge of cancer control at the
Bureau of State Services, came for advice about X-ray
mammography and its application .
Soft-tissue X-ray examination of the breast was
suggested by Dr . Stafford Warren as far' back as 1930
but remained unused until it was revived by Dr .
Gershon-Cohen in Philadelphia and Dr . Robert Egan
in Houston during the )950's . Egan's efforts in a
primary cancer center gained the particular attention of
influential radiologists . Tests for clinical reproducibility and reliability were conducted, and training programs in the technique were initiated with the help of
the cancer control activity of PHS .
My conversations with Robbins, Mr . William
Haenszel, and Cutler resulted in a plan of applying the
method in the screening of symptomless women for
breast cancer, the most common neoplasm of our
female population . Endicott was receptive and had
funds to allocate toward the development of a contract
for the purpose . For the field trials to yield meaningful
numbers, they would cost several million dollars and
take a minimum of 5 years, involving some 60,000
women assigned to two matched groups . One attraction of such a study was that it would be the first
biometrically designed field trial of a diagnostic procedure for cancer . Even vaginal cytology for cervical
cancer did not have a designed field test, since it came
JNCL YOL . 62, NO. 5 . MAY 1979

nc, hrfore such refinements were considered

n.

J support assured by Endicott, we approached

ir., lic.rlth In,ur:+nce f'lan (HIP) in New York as the
pr .-~iLle prirne contractor . 'I-here existed a population
undcr a turificd medical care system with its central
re ords under a capable statistician, Mr . Sam Shapiro,
s. ho h .rd shown his talents in large population studies .
A r .rdinlogist for the group, Dr . Philip Strax, had
knowledge of X-ray mammography and was enthusiaaic about its possibilities . Our greatest concern was
s.hether the surgeons of the system could be induced to
operate on the basis of radiologic indications in the
ab,ence of palpable masses . This issue was resolved by
the caieful, low-key persuasions of Dr . Louis Venet
and his wife, Wanda, who was a nurse .
The study was conducted after I retired in 1963, but I
served on its advisory committee until the results were
in . As we had hoped to predict, a reduction in
mortality of about 25% was achieved by the application
of X-ray mammography and physical examination to
the 30,000 women in the study group, as compared
ith 30,000 matched controls (64, 65).
The HIP study of X-ray mammography was the
basis of a network of breast cancer detection centers
rganized and operated as combined NCI-ACS enterI,ies under the cancer control program initiated in
1912 . This method of detection came under criticism
.b n B ;:ilar's (66) analysis indicated that no benefit
h :,J bccn demonstrated in women under 50 years of age
;,ri th it the risk of breast cancer was increased by
.diz.tion . Three advisory committees were appointed
, su : .% the epidemiologie, radiologic, and pathologic
lI :ec<s of the problem . Their reports to NCI agreed
cirh 1lnil ;,r's recommendations that the procedure
should iercly be done in asymptomatic women under
50 yeus of age . Exceptions are now limited to those
. ; :h a history of breast cancer in their mothers, sisters,
or 0rts,eF.es . The ACS, however, wanted to include
lt ,,:mcn 35 years and older .
I rc .+s on the NCI Cancer Control Advisory Commit.,t the time the original decision to establish the
.at . .,ncer detection centers was made. It was then
.idcnt . as Bailar was to point out, that women under
;~0 , c .rrs old in the HIP study were not demonstrably
h :nr.fir ;rd . Nerertheless, the decision to extend the
; ro- r! ,re to age 35 was rationalized by a number of
nts that too few younger women were included
:te 1fIP study for the negative conclusion, that
oi,iosnntnt in radiologic techniques would yield
greater accuracy of detection, and that it was important
to Cnlist younger women in order to establish their
subsequent health habits regarding their breasts . The
r.rdiologic hazard was considered to be minimal and to
be further reducible by improved equipment . Ob%iously, all these features should have been actually
tested before being assumed . The set of considerations
is different for the analytic research mind and for the
pioponent a rrd activist of health programs . The proper
point of equilibrium remains in the rcalm of social
!%r'cistons .
1~(.I . vot. 62 . NO . 5, MAY 1979

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CANCER CHEMOTHERAPY NATIONAL SERVICE

CENTER
Experimental cancer chemotherapy was a research
component of NCI long Ixfore its expansion as the
CCNSC (1). Dr . Murray J . Shear's Laboratory of
Chemical Pharmacology was the main focus, with Drs .
J . L . Hartwell, J . Leiter, M . Belkin, and A . Goldin
heading various aspects of the activities .
Two historical, administrative accounts of the
CCNSC are available . One is by Endicott (67), its
creator and administrator ; the other is by Zubrod and
his associates (68), 10 years later . Both accounts are full
of facts about the design and operation of the program,
the consultants and panel chairmen, the fiscal allocations, the number of compounds tested ; the number of
animals used, and the drugs introduced into clinical
practice. Both accounts mention little about the men
and women of the staff that made the wheels turn, and
both avoid conclusions whether the wheels were worth
turning in the first place, much less whether the results
were commensurate with the efforts.
Emphasis on cancer chemotherapy was not widely
greeted among scientists or clinicians . It was highly
promoted by a few influential people, especially Dr .
Sidney Farber of Boston and Dr . Cornelius P . Rhoads
of New York and their allies . The leadership of the
chemotherapy drive was taken over by the well-known
alliance of Farber, Mrs . Mary Lasker, Congressman
John Fogarty, and Senator Lister Hill .
In 1953 the campaign for chemotherapy obtained
earmarked funds, and for a couple of years the standard, tried and true, conservative methods were used :
more grants, more announcements, a newsletter, and
one professional position attached directly to the Office
of the Director . For entrepreneurs like Farber and
Lasker, these were laughable inadequacies about which
they did not laugh . A top-notch expeditor was assigned
from his post as deputy to the NIH grants division, not
to expedite but to recreate . And Dr . Kenneth Milo
Endicott certainly did all that, in spades. Every step, of

Frerar 2.-TTe trginnings of the chemotherapy sting program .

J . L . flanwell (right) and assisrem at IdCI, about 1950 .

In the Middlet" NCI, 1954-63 1305

course, was c:ucfully rcviewed with Fanccr, who remained chainnan of the executise bo ;rrd of the cnlerprise as well as a mentbcr of the National Advisory
C.1ncer Council .

CCNSC was a completely new slructure, which from

the beginning irvolved etrry official and private agency
that had anything to do with any aspect of its mission .
The Food and Drug Administration (FDA), the Veterans .adn7inistration, the ACS, and others were invited
to participate . \1'ilhout much exception such participation was ceremonial, but it served the purpose of
creating the image of an overwhelming national mandate .
Cancer in the mid-1950's was, clinically, a surgical
monopoly. Surgical failures were referred to radiologists, often with in3tructions about where and how
much radiation to administer . Patients not eligible for
surgery or radiation were of no interest to internists or
anyone else . A hospital bed allocated to a terminal
patient with cancer was considered a waste, medically
or instructionally, and parents of children with acute
leukemia were told to take them home . Perhaps the
greatest effect of the chemotherapy program was to
enlist internists in the care of advanced neoplastic
disease and to train them in scientific methodology of
clinical trials .
CCNSC organized every physician interested in cancer into study groups . The first such group was headed
by Dr . C . Gordon Zubrod, brought in to be head of the
clinical cancer activities of the Clinical C.enter . He and
his young associates, especially Dr . James Holland, Dr .
Emil Frei 111, and Dr . Emil J . Freireich, with the direct
participation of Schneiderman and access to all the
resources, formed the Eastern Cooperative Cancer
Group . This group retained its leadership from then
on, and its alumni later headed the large clinical activities in Buffalo, Houston, and Boston .
A clinical cooperative was organized around the
Memorial Hospital in New York as one of the leukemia groups under Dr . Joseph H . Burchenal, and one
cooperative was centered at the M . D . Anderson Hospital for Cancer Research in Houston . As work spread,
additional groups were formed and demanded admission to the program, so that limitations in the size and
number became serious problems . The real aim of the
clinical groups was to test chemicals that were found
actice against cancer in animal screening systems, but
the number of such chemicals was much smaller than
anticipated . Many, groups ivere left with comparisons
of close analogs or minor modifications of dosing and
scheduling the agents .
Clinical research was still new at NIH, and the
lawyers began to raise warnings that such research
under contract would make NIH liable to litigation .
All clinical research, it was decided, should be supported by grants . But the grant system at NIH was in
different hands, not a bit sympathetic to the CCNSC
program, and with the review study section chaired by
Dr . Alfred Gellhorn, an open opponent to biometrie
clinical trials . The cloak of eonfidentiality, ahrays
comeniently a .ailable, was thrown oser the grant

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reticw mechanism, and considerable rcarrangement

was necesc ;rn to get the clinical aslec(s back in phase
with the CC:1SC: objectives .
It was ob .ious from the siart that surgeons had to be
induced to participate if the program were to involve
any but the semiterminal cancer patients (69) . Several
young surgeons, such as Dr . Daniel Martin and Dr .
George Dloote, were more than willing, but what was
needed was a respected elder statesman . Dr . I . S .
Ravdin, professor of surgery at the University of
Pennsylvania, ex-brigadier general, and consultant tb
President Eisenhower, occupied this role . The little
general, by then past his prime, would charge down to
Bethesda - with what he called his jar of grasshopper
suppositories and rearrange a procedure or two for
what he thought would be greater efficiency .
Endicott was exquisitely aware of the need for
continual stroking of his stable of chairmen, consultants, and legislative supporters . The latter had a
direct hotline to him, and he also reported to them
regularly. His path to the Office of the Director of the
NIH was well worn . Farber in Boston, Ravdin in
Philadelphia, and Lasker in New York were on his
permanent beat, and lie would take a minion or two to
sit at the feet of the masters and admire unreservedly
their wisdom and their leadership . To a great extent
this was all necessary-a fact of life that scientists at
the working level so conveniently forget .
One of the yields of the CCNSC program was a more
rapid introduction of statistical concepts and designs
into clinical investigations . Schneiderman provided
this impetus ; his acceptance was facilitated by Zubrod,
who on advice from Dr. E . K . Marshall took a course
in statistics himself .
The need for quantitation, uniform criteria, and statistiad planning and analysis in clinical research as
well as in all science should need no defense . Yet there
are the nagging facts that no major discovery can be
auributed to more than a modicum of these features .
No Nobel prize seems reasonable to anticipate for a
protocol designed by a committee, tested under doubleblind conditions, and analyzed by a computer .
It is a fact that the major advances in cancer chemotherapy were made by astute clinicians without a single
test for probability and reported without a single error
of the mean . Some examples include : a) the effects of
castration and estrogens on disseminated prostate cancer, for which Huggins shared a Nobel prize (70) ; b)
regression of a lymphosarcoma in a patient inoculated
with nitrogen mustard by the Yale group (71) ; and c)
cures of women with disseminated choriocarcinoma
with the use of methotrexate by Li, Hertz, and Spencer
(72).
Only when the effects are minimal and the differences small does biometric design become essential to
separate fact from wish . One can argue whether it is
worth the expense to show that nitrogen mustard is no
better than a close analog or that most androgenic
steroids yield similar effects on breast cancer .
One occasion on which biometry was essential was
the resolution of the place of nitrogen mustard followJ7:C1 . VOL . 62, NO . 5 . MAY 1979

()

tT

1306 Shlmkln

ing resection of lung cancer . Some clinicians were

espousing its i,se with all the comiction of their
hallo ..ed surgical reputations . The use of nitrogen
mustard was found to be baseless under rigid eonditions that were themschrs more informative than the
results . The first stage of the study, on patients in the
Veterans Administration hospital system, did not in-

clude double-blind design because the surgeons were

skittish enough with randomization alone . In no time
many more untoward effects were being reported in the
HNj-treated patients . The chairman of the study now
agreed to use the double-blind technique with HN=
and saline, except that both treatments were saline
alone. The number of complications equilibrated, but

at the level previously recorded for the group given

HN 2 -an excellent- example of an observer's placebo
factor . Subsequent comparison of HN2 and saline
showed no benefit attributable to HNr, and this toxic

addition to major surgery disappeared for the nonce . It

recurred during the later days of polypharmacy but
under better conditions of observation .
CCNSC day-to-day operations were in the hands of
the permanent staff, mostly recruited from other areas
of NCI . Dr . Joseph Leiter, who had been involved in
experimental chemotherapy in Shear's laboratory, applied his experience to the laboratory aspects, from
procurement of chemicals to their screening for chemotherapeutic effects in animals bearing transplantable
tumors . Such transplantable tumors were selected after
a thoughtful review of available information by Gellhorn and Hirschberg (73). The size of the program
exceeded the mouse supplies available at the time, and
new breeding colonies had to be established and
supported .
The volume of data being ground out presented a
serious logistic problem itself . More contracts were let
to computer firms to organize, with many stops and
starts, the figures and findings . Massive tomes of tables
issued .fArth, soon raising the hackles of cancer researchers who would not read them or who could not
understand the value of such communications .
I was appointed Assistant Chief for Clinical Activities of CCNSC, a title that I found was essentially
empty . The clinical activities were in the hands of
people actually doing clinical work ; their funding was
from the grants area of NIH, and they needed me not
at all . However, preclinical pharmacology needed buttressing, and Dr . Gustave Freeman was recruited for
this area . This was before the revised FDA regulations
became more stringent, and the requirements for the
CCNSC-sponsored chemicals were, in effect, left to the
CCNSC . This convenient but inconsistent pattern persisted by the assignment of an officer of NCI to FDA to
supervise oncologic drugs, which he did by looking the
other way . Many years later the relationships between
NCI and FDA became strained on this point, long after
CCNSC had disappcared and a whole Division of
Therapy had been evolved .
Freeman and I did get a chance, which we could
have done without, to launch the endocrinology portion of the cancer chemotherapy program . Although
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the effect of endocrine ablation was the opening

chapter of the modern cra of cancer chemotherapy, the
origin :J CCNSC did not include hormones among its
considerations . Farber was devoted to antifolics and
other antimetabolites, and Rhoads was interested in
alkylating agents . But Lasker had a friend in Los
Angeles who espoused estrogen castration for men who
had had heart attacks, and suddenly an item of $5
million for hormone therapy research appeared in the
C.ongressional budget for CCNSC.
The clinical groups at that time did not include
endocrinologists, so they had to be recruited and the '
flow of expensive steroids from patent-protected sources
had to be established . The two target diseases, of
course, were breast and prostate cancers, both well
established as neoplasms that retained some hormone
dependence. An endocrinologist, Dr . Erwin P . Vollmer
(74), was enticed away from the research laboratories of
the Naval Medical Center in Bethesda, and a series of
organizational meetings followed .
Dr . Albert Segaloff of the Ochsner Clinic in New
Orleans emerged as the leader of the Breast Cancer
Cooperative Group . They had more demands and more
complaints than was their share . Attempts to create
two breast cancer groups to provide some competition
of ideas were unsuccessful . Years later, the main
achievement was the testing of a whole series of
androgenic steroids (75), none of which were really
superior to the original testosterone . The data replicated closely the analysis of case records, made without
statistical design, and reported by the American Medical Association a decade, before (76) .
The other endocrine group dealt with prostate cancer. There the ideas were so limited that the major trial
was on diethylstilbestrol (DES) in massive amounts up
to several hundred milligrams per day . Predictably, no
additional benefits were elicited by the large doses .
Later, however, large doses of DES were suspected of
accelerating the mortality from electrolyte effects on
old men with damaged cardiovascular systems . A study
by Bailar et al . (77) firmly established that DES in
large doses indeed accelerated mortality, and the treatment of patients with disseminated prostate cancer
returned to the regimen originally proposed by Dr.
Charles Huggins.
My second real participation in the clinical program
of CCNSC was in initiating the adjuvant use of chemorherapeutic agents following surgical resection for
cancer .
The idea that a minimal amount of disease, such as
that following resection for curative intent, would be
more responsive to chemotherapy was evident from
experiences with microbial antibiotics and from the
experimental work on cancer by Dr . Warren H . Cole
and by Martin . Endicott thought that it was a reasonable addition to his program, and Ravdin took on the
task of convincing his surgical confreres . Clinical trials
based on carefully detailed protocols were reviewed by
study sections, councils, and appropriate professional
bodies before being announced in 1958 (69) . The
Veterans Administration system, headed by Dr . Lyndon

In the hliddle ; NCI, 1954-63 1307

Lee, was particularly contributory in studies on cancer

of the siomach, recntm, and lung . Their census of
women, howecer, did nut allow participation in studies
on cancer of the breast .
The adjuvant chemotherapy swdies tnobilized interest of the surgeons, making available patients with
cancers less advanced than those usually seen by
internists . We were hoping to extend biometrically
designed evaluations to surgical procedures, such as
radical versus simple mastectomy, and to the combination of radiation therapy and surgery . Radiologists
proved more recalcitrant than surgeons, and it was well
into the next decade that such investigations were
finally and tenuously instituted .
Adjuvant chemotherapy during the early years was
limited to a few postoperative squirts of an alkylating
agent . There was no evidence of increased survival or
delay in recurrence in any of the series except for breast
cancer with limited axillary involvement of lymph
nodes, where an effect was shown by 1961 . This effect
was extended and resurrected with considerable hoopla
much later (78) .
The concept of adjuvant chemotherapy is good . All
we need are better antincoplastic chemical agents!
CANCER CONTROL
It was obvious by 1957 that the fortunes of cancer
control, called the Field Investigations and Demonstrations Branch, were on the wane at NCL As long as
Scheele and fieller directed the activities and were
comfortable with the way things were done, they were
a safe side current, having their own review mechanism and direct relations with State departments of
health for cancer grants and with medical and other
professional schools for teaching grants . But Dr . James
A . Shannon, Director of NIH, was never happy with
the public health aspects of categorical diseases, and he
supported ihe view of a Congressional review committee that opined that these features of the program
belonged "downtown" with the traditional public
health divisions . I suspect that the committee was
coached, subtly or otherwise, to reinforce Shannon's
desires . Had he given support to public health activities instead, the recommendations probably would have
remained unrecommended .
In any event, by 1957 there began a slow attrition
and transfer of activities from NCI to the Bureau of
State Services where, under the Division of Chronic
Diseases, funds for State disbursement were considered
more tidy than from NIH . Only the Mental Health
Institute, with its own powerful lobby group, refused
to go along . This led to the separation from NIH of
the Mental Health Institute, blossoming as the impossible acronym ADMHA, or Alcohol, Drug, and Mental
Health Administration .
Kaiser and his staff tried to hold on but it was an
impossible job, and the finis was written when Endicott took over as Director of NCI from Heller . Endicott
was an expert in smelling shifts in the wind and
accommodating upper echelon wishes . It fell to my lot

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to execute the coup de grace, and I did not like it at

all . Bring eliminated was as painful for Kaiser in
Bethesda as it was for me in San Fr :utcisco .
The cancer control activities had gathered a lot of
barnacles during the decade of their existence, and
some of the barnacles were even older, having been
inherited from the pre-World War 11 days . Many of the
activities, in the cold light of critical review, were
deficient in evaluation . There was no way to evaluate
what good, if any, had been accomplished by the
annual handouts for presumed cancer teaching to
medical schools, dental schools, and some nursing
schools . The same questions, of course, could have
been asked of the traditional research grants, with
equally embarrassing silences for answers . But research
was not under the gun and cancer control was .
The program of the Field Investigations and Demonstrations Branch that could be identified as research
and maintained with the NCI turned out to be a mixed
bag . Occupational and industrial investigations, such
as the surveys of the uranium miners in the UtahColorado plateau in combination with sputum cytology, appeared useful . And indeed, they did lead to a
definitive conclusion of greatly increased risk for lung
cancer (79), as coul have been predicted from the 19th
century experience in Germany . In 1960, of course, the
Government was excluded from industry, and one of
the few effective forays in that direction so far as
carcinogenesis was concerned was by Dr . Thomas
Mancuso in Ohio, for whom a career professorship was
obtained through the NCI .
The PHS had a special building erected in Hagerstown, Maryland, where an ecologic approach was
planned for identifying radiologic and chemical
sources of hazard and relating them to occurrences of
cancer . Alas, methodologically the study was faulted
and had to be discontinued, but not until a premature
journalistic report had emanated regarding a cancer
cluster in the high school graduates of the area (80) .
The branch also had three commissioned officers
deployed in Berkeley, Boston, and Pittsburgh ; two of
these were contributing worthy work .
. Cancer control "downtown" acquired a new leader
in the person of Robbins, whose approach to cancerand life-was devoted and intense . He did not know
much about cancer but he would learn, and immediately he developed allies among the establishment of
the ACS and the general practitioners . The advisory
committee to the program operated in a careful manner-careful not to rock any boat of medicine or its
institutions . At appropriate points, quality was invoked if things were going too fast, a demonstration
that the worst enemy of the good is the perfect . If
cytotechnicians did not stay with their work, the
answer was more education ; rapidly it became obvious
that women with 2 years of college had even less
interest in straining their eyes over smears than women
just out of high school . Self-obtained smears, under the
criteria of the advisory group, were not worthy of
consideration .
Robbins was committed to the view that, given the
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1308 Shtmkln
correct information, humans would do what was right .
Informed private practitioners were his target, and
front thence all blessings would flow . The cssential
approach was the traditional medical one: detection of
overt disease at an "earlier" stage . Prevention by
avoidance of causative exposures or the identification
of precursors became of primary importance for Robbins much later, when he developed Health Hazard
Appraisal (8l) .

The fact was, and is, that categorical diseases do not

fit well into public health or preventive medicine . The
same difficulties that were encountered by cancer conuol under the Bureau of State Services became evident
over a decade later when Regional Medical Programs,
designed along categorical disease lines, found itself in
the environment of more general public health as
outlined in Comprehensive Health Planning .
I was informally appointed to act as liaison with the
Cancer Control activity . Robbins was so intense that
no amount of argument could persuade him that his
"shop talk" seminars for general practitioners were not
going to be rewarding, or that there were any other
approaches to cancer than through the medical establishment . Ife did visit the NCI frequently and consulted widely with technical people ; certainly he admitted that he had a lot of learning to do, and he was
willing to learn .

FIELD STUDIES AREA

The period between 1957 and 1960 at NCI was one
of considerable administrative disarray occasioned by
programmatic shifts and musical chairs for its top
personnel .
Scheele was succeeded as Surgeon General by Burney .
Surgeons general were considerably more important
then than now, and they had influence on research as
well as othtr health programs . Shannon, the dynamic
NIH Director, probably could have been designated
Surgeon General but preferred his NIH post, He was
rather contemptuous of Burney as he was of most
people who did not meet his standards, and this
attitude did not improve relationships between NIH
and PHS . Another factor was that Heller was also a
andidate for Surgeon General and soon thereafter was
elevatedto flag rank, the first Institute Director to be
named Assistant Surgeon General . He was offered a
better-paying position with the ACS and did accept the
post of president of the Memorial Hospital-SloanKettering Institute in New York in 1960 .
The upgrading of rank at NIH started a competition
that saw Endicott leaving the CCNSC in 1958 to
become a flag-rank Associate Director of NIH until his
return to NCf as Director in 1960 . Dr . Stuart M .
Sessoms replaced Endicott at CCNSC, but in 1962
Sessoms also was promoted to Deputy Director of NIH .
Mider, who had headed the Intramural Program and
was increasingly unhappy at the turn of events at NCI,
Was made Director of Laboratories and Clinics at NIH
in 1960 . All of these changes produced uncertainty and

confucion aniong chiefs of univities who reported to

these individuals .

When the dust settled in 1960 and Endicott became

the fourth Director of NCI, he invited me to lunch . lie
outlined his plans for a rcorganiuuion of the NCI into
four areas : intramural research, grants and training,
field studies, and collaborative research, each to be
headed by an associate director . He offered me the
Field Studies area and I accepted . The area was to
include biometry, epidemiology, carcinogenesis, and
diagnostic research, as well as Hueper's section on
environmental cancer . I was given authority to begin
recruiting additional staff, including consideration of
some persons about to be displaced from other NIH
activities. The latter included Dr . Eli M . Nadel, who
was being relieved as administrative assistant to the
NIH Deputy Director, and a few lost souls of the
dismantled Cancer Control Program who were still
lingering at NCI . Exploratory nibbles for reassignment
were also received from some intramural staff ; a few
were made directly and more came from supervisors
who wanted to see them placed elsewhere . Finances
were no problem at that time.
We planned an activity that was not restricted to
administrative arrangements ; Endicott agreed that Field
Studies should have functional laboratories of its own,
with working scientists extending their interests and
supervising contracts for collaborative research . Endicott, an alumnus of the NIH grant program and
innovator of the contract arrangements at NIH, was
somewhat dubious . He predicted either actual or implied conflicts of interest but was willing to explore
this new approach .
I inherited from Kaiser, who had headed the Field
Investigations and Demonstrations Branch, a Mussolini-sized office in a rickety building in Bethesda- I
then started negotiating for laboratory space in yet
another building off the NIH campus, reviewing the
bits and pieces left of cancer control, and recruiting
additional staff.
The negotiations for the Auburn Building, across
from the firehouse in Bethesda, for use as a laboratory
dragged on for months . Finally, I asked for an analysis
of the delays from my administrative officer who
provided me with a memorandum outlining 16 separate steps of review and approval that had to be
completed, such as electricity, plumbing, and parking .
I forwarded the analysis with the suggestion of facilitating the process by simply deleting all even-numbered steps . The replier was not amused and suggested
that I appoint a coordinator, which would have added
one more hurdle .
The laboratory space was thoroughly inadequate,
especially because Ilueper laid claim to it all . When
told that Drs . John and Elizabeth Weisburger and their
associates had to be accommodated there, he decided to
stay at his facilities in the Clinical Center . His administrative return to the intramural area came quickly
after he learned that Dr . Paul Kotin was being recruited for the Carcinogenesis Branch . Hueper considered Kotin as his student and could not tolerate a

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O
F
J
0

In the Middle ; NCI, 1954-63 1309

Flevzr 3-Staff of the Field Studies Area, NCI, Bethesda, Md ., 1963 . Front row, left lo zight : R . J . Taylor, J. H. Weisburger, R . w . Miller,
E . Young, M . B . Shimkin, E . Nadel . Second row, left to right : J . Mahoney, {4. Haenszel, S . J . Cutler, J . C. Bailar III, H . Falk, M . A.
- Schneiderman, P. Kotin . H . F . Kraybill, O . .Scott .

position he considered to be lower . I-lueper's defection

freed some precious space that could accommodate
more biochemists and immunologists .
The Biometry Branch was placed under Mr . William
Haenszel, .the experienced senior professional, and the
program continued on an expanded scale . Haenszel
himself became intrigued with the effect of migration
on cancer risk (82) and developed an international
series of investigations made possible by the availability of the blocked currency under provisions of PL 480 .
His carefully designed, meticulously pursued studies
involving European and Japanese migrants have shed
much light on environmental factors in cancer of the
stomach, intestine, nasopharynx, and breast .
The Epidemiology Branch had to be recreated anew .
Gilliam retired and joined the faculty of Johns Hopkins School of Public Health, and nearly all his coterie
of professional rank left for elsewhere, though Dr .
Miriam Uanning stayed in Boston . Dr . Robert IV .
Miller, a pediatrician by training who had experience
in Japan with the Atomic Bomb Casualty C.ommission,
consented to fill the post . Miller was a thoughtful
man, interested in hypotheses and individual work
rather than ptogram development . He soon contributed
several novel observations, such as the relation of
congenital defects and neoplasia (83) . As an example,
he noted that Wilms' tumor was associated with
aniridia and hemihypertrophy .

http://legacy.library.ucsf.edu/tid/urc71d00/pdf/

Miller succeeded in finding Fraumeni, an internist

who joined him from New York . Fraumeni decided to
make epidemiology his career and complemented Miller
by being interested and able to undertake programs
that Miller considered pedestrian and unworthy of his
time .
Nadel rearranged the diagnostic testing that was
done by the old Field Investigations and Demonstrations Branch (&/) . A half-dozen vaginal cytology projects scattered across the land demonstrated the basic
difference between research and health programs . Results of the vaginal smears were sent to headquarters, .
where stacks of thousands of reports accumulated . As a
monitoring device they probably served their purpose,
but as useful information they were of no value . Our
recommendation that further analysis of the reports be
discontinued was accepted except for reports from
Rhode Island, the bailiwick of Congressman John
Fogarty . His untimely death made a summary from
Rhode Island also unnecessary .
The diagnostic area that interested me most was the
attempt to develop an automated cytoanalyzer (85) .
Money had been extended by driblets to small companies with equivocal results, The effort obviously
needed a large allocation to the most competent
engineering concern, plus discontinuation of attempts
to copy by computer the qualitative tinctorial experience of pathologists . Cancer cells had physical
JNCt, S'OL . 62, NO . 5, MAY 1979

1350 Shlmkln
propenics that lent themsel .rs to three-dimensional
eomparisons rather than dependence on the classical
tcchniques .

N ;idcl .%as an expert in writing rnemoranda of many

single-spaced pages and keeping several committees in

constant motion . One day it was announced to me that
his aaivity would be transferred to the intramural area .
This provided better laboratory backup for diagnostic
research but effectually terminated any plans for field
trials of diagnostic procedures.
The organizational phases of the Field Studies area
were barely completed before another administrative
requirement was imposed : additional review and approval by outside committees . This development involved the whole NIH as a response to a Congressional
mandate for wider participation of tlte scientific community in the affairs of NIH .
Three committees were appointed-for carcinogenesis, biometry-epidemiology, and diagnostic research .
The nominees were picked by the staff and reviewed
for eligibility for government assignments, which still
included fiscal purity and no involvement with what
were listed as subversive organizations . We were, of
course, aware of the informal S-lists at the NIH and
PHS levels that kept some otherwise desirable nominees
from consideration . This became a mini-scandal later
and contributed to the more open processes, dubbed
the "sunshine" regulations .
Review committees appointed by the people they are
supposed to review leave something to be desired as to
objecti .ity, but they are convenient for program directors . Even better, of course, would be their absence
because the process of preparing agenda, duplicate
documents, and various hospitality arrangements for
the meetings is burdensome . We accommodated, but
the value of the additional steps, except as a form of
participatory democracy, was hard to demonstrate .
CARCINOGENESIS
Endicott continued the previous practice of having
no staff meetings with his program leaders at which
administrative or functional goals could be discussed .
Rather, decisions regarding budgets and organizational
alterations were announced . Thus I learned only after
the fact that the Diagnostic Research Branch, under
Nadel, was to be transferred to the intramural area .
Neither was I pleased by hearing that the expanded
viral oncology program had been placed under Collaborative Research, which separated it from the other
important etiologic area of chemical carcinogenesis . It
seemed that factors other than science took precedence
over research on causative agents .
In the late 1950's, the most compelling approach to
the cancer problem was viral oncology . The approach
was made possible on a large scale not only because
accumulated scientific knowledge made such expansion
desirable, but also because the resources were there,
ready for exploitation . These resources were the laboratories and the talents left over from the successful foray
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dation Against Infantile Paralysis . The same guns now

could be trained against neoplasia . In eontrast with
this affluent state in virology, chemical ealcinogenesis
had been in the doldrums for over a decade . The
laboratories of the Chester Beatty Institute in Great
Britain were leaders in the area, and the McArdle
Laboratory in Wisconsin was a prime contributor to
the knowledge on metabolism of carcinogens . Dr .
Philippe Shubik's laboratory at Chicago Medical
School was devoted to the testing of chemicals for
carcinogenic activity . Dr . Norton Nelson's Department
of Industrial Health had important interests in cancer,
but it was diluted in its broader objectives . Dr . Arthur
J . Vorwald, an alumnus of tuberculosis research, was
developing inhalation studies on beryllium in monkeys, but this was a narrow segment of the problem .
Kotin at Southern California, with his chemist associate, Dr. Hans Falk, was involved in a broader
program of carcinogenesis that seemed most applicable
to what was needed .
Our resources, obviously, were very limited and not
backed at the NCI except by Hueper . If chemical carcinogenesis was to take its proper place in cancer
research, an expanded allocation of funds and the
creation of additional facilities were essential . The
matter of funds was quickly resolved . I was even called
to appear before Shannon and Mider, who were sufficiently impressed by the vistas of environmental carcinogenesis to back our budget request . The strategy, as
worked out with Endicott, was to recruit Kotin and
Falk to head the Carcinogenesis Branch and to get
Shubik on the National Advisory Cancer Council to
backstop the policy of developing this area . Then the
idea was to develop several new centers for carcinogenesis work and to use the conceptual framework of
pharmacology .
The placements of Kotin and of Shubik were successful, but the subsidy of new centers by,contracts or even
grants was not . Shubik's own laboratory was recast in
funding by a large contract . Eventually, it was successfully transferred to Omaha, Nebraska, where it still
represents a prime center for the study of carcinogenesis . Additional money was made available to Nelson,
and eventually the laboratories at Stirling Forest in
New York expanded their carcinogenesis activities
under Dr . Benjamin L . Van Duuren . But long-term
commitments for new centers under scientific supervision and participation of research pharmacologists
could not be made. It was obvious that straight
toxicology, in which chemicals would be given by
some systematic procedures spelled out by a central
coordinating group, would be of little interest to
imaginative research workers . Such by-the-numbers
approaches without research input and differences of
opinion and approach were simply premature . It was
also obvious that the number of chemicals to be tested
would be an unlikely task unless shorter, perhaps in
vitro, procedures could be devised . This again required
full-time, long-term devoted attention to the problems
by scientific talent that would not be happy with
routine testing.

In the Middle : NCI, 1954-63 1311

An interesting experience occurred with a modest
mtract to test a seriesof alkyl :rting ;igerits by the lung
tumor response in strain A mice . This is a shorbterm
in vivo procedure and a fine indicator for this class of
compounds . Close supenision over the activities of a
commercial laboratory and responsibility for the analysis of the results and pteparation of the final report
had to be assumed (86) . The results certainly seemed
worthy of inclusion as a part of the continuum for
testing potential chemical carcinogens, but this was
not to be . Instead, emphasis was placed on life-term
observations on mice and rats, with impossibly complicated records including histologic section on 40 tissues
of each of 200 animals! No wonder that a decade later
only a small fraction of the chemicals proposed for
testing was completed, with equivocal results providing additional fuel to criticisms by the entrenched
environmentalists to whom every hepatoma and every
chemical represents a virulent danger .
Viral and chemical carcinogenesis are not two worlds
apart . Both involve similar intracellular changes, and
research on both should have been united . 1'et research
was separated and the hiatus between chemical and
viral interactions remains-administratively, budgetarily, and scientifically .
Soking problems by contract support is simply a
bad idea . Research support should be made for long
periods and truly decentralized from control by ever
younger, less-experienced headquarters personnel . Stability and continuity are as essential for research as for
other human endeavors, especially for those deemed
needed by society rather than those chosen spontaneously .
The lesson remains unlearned : New long-term centers for carcinogenesis research have to be established .
The reliance on contracts, annual reviews, and standards set before they are soundly tested leads to
frustration and failure .

term Iarge-scde tissue culture had abated, but Dr .

Virginia J . Esans and her group continued to add
important contributiorts to the field . Bicxhemistry after
Dr . Jesse P . Greenstein's death seemed to be in the
doldrums so far as applications to cancer were coneerned .
The intramural programs were freshened by younger
research workers . Perhaps the most novel contributions
were in the reviving field of tumor immunology, where
Dr . Richmond T . Prehn (89) and Dr . Donald L .
Morton (90) were showing evidence of immune host
response to induced sarcomas and to spontaneous
mammary tumors in mice . Experimental embryology,
which a priori would seem to have direct application
to cancer as a model in tissue differentiation, was being
developed by Grobstein (91) . However, he did not
apply his techniques to neoplastic growth and left for
the academic world before the field could be developed
at NCI .
Viral oncology was in full bloom, and a separate
branch was created for Dr . Ray Bryan as well as a
study section to promote grants in that area . The most
prominent virologist on the NIH campus was working
in the Institute of Allergy and Infectious Diseases
(NIAID) in a special biohazard laboratory building . He
was Dr . Robert J . Huebner, a recognized authority on
rickettsia and viruses and a dynamic, imaginative field
investigator whose many ideas required patient and
critical collaborators. These he had in Dr . Karl Habel
and Dr . Wallace P. Rowe (92).
Huebner, a driving entrepreneur, had collaborated
with NCI surgeons in attempting to use viruses for
oncolytic effects on cervical cancer and was well aware
of the potentials of his knowledge and facilities in the

OTHER NCI AREAS

Ft By 1960, the intramural area was headed by Dr .
~ . Eugene J . Van Scott, a low-profile dermatologist .
Sessoms had the virus program added to his CCNSC
responsibilities (now called collaborative research), and
Meader continued as head of the grants area .
7% In 1960 many of the old guard of original research

workers were still at NCI . Dr. Howard B . Andervont

continued to perform his careful experiments on carcinogenesis in various strains of mice . A major endeavor
involved interstitial cell testicular tumors induced in
mice by diethylstilbestroL lie invited my collaboration
and that of my son (87) . Dr . Lloyd W . Law (88)
continued to perform his meticulously designed investigations in experimental leukemia .
The pathology morphologists, Dr . Harold L . Stewart
and Dr . Thelma B . Dunn, added age and experience to
.their authoritative reviews and cooperative studies . Dr.
Clyde J . Dawe extended interests to tumors in lower
animals and began to detelop eomparatixr pathology
becond the usual laboratory animals . Interest in long-

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F1Gt'Rt 4 .-N' . P . Rowe (left) and R . J . Huebner of the National

Institute of Allergy and tnfectious Discases, about 1950 .

JNCt. 1'OL . 62, NO. 5 . 4sAY 1979

1312 Shlmkin

rancer program . After diplomacy Irenceen institute

dnc, inrs, funds i rcre transfcned from \Ca to NIAID to
arrommodauc Huebner's activitics . The formula both
ditidrd and ttcfied super .isinn, and a wild horse like
Hucbncr was hard to ride . Eventually he was trans
ferrcd to NCI . Bryan was shelved as a special assistant
to the burgeoning viral oncology program . These

ctents, however, stemming from the scientific eonsensus that virology would solve the enigma of neo-

plasia,

really

peripatetie

belong in the later 1960's . Iiuebner's

contract

arrangements finally involved such

large budgets that they came under review, and a

critical

report of a special committee of the National

cademy of Sciences was issued . Huebner's oncogene

theory (93) of an RNA viral particle as part of the
A

mammalian genome temains a viable research hypoth-

esis, and the contributions from him and his coworkers

are among the more important oncologic work of that
time .
The quiet work of Drs . Sarah Stewart and Eddy
demonstrated carcinogenicity of the polyoma virus in
several species and the oncogenicity of simian virus 40
in hamsters . Stewart was not a tidy investigator, and
the numbers in her tables submitted for publication
often did not add up correctly . Iier earlier reports of
the induction of many types of neoplasms with extracts of mouse parotid tumors maintained in tissue
culture simply were not believed . Neither were the
parallel results being reported by Dr . Ludwik Gross in
New York, who originally discovered the parotid tumor virus . Pathologists were called in to diagnose
the sections, but even their verifications were not
accepted as convincing until other investigators replicated the major features of the work . Eddy, Stewart's
collaborator in the Division of Biological Standards,
had even a harder time and was questioned as to what
she was doing in the cancer field . Here was undoubtedly one example of prejudice against women,
who were not accorded the recognition they deserved
for their novel contributions .
The clinical area by 1960 was dominated by chemotherapy under Zubrod . Dr . Albert Ketcham had replaced Dr . R . R . Smith as head surgeon but had
t'hitiated no new investigations by 1963 . Radiation
therapy did not manifest itself except in the contributions of Dr. M . M . Elkind (94) in radiobiology.
Endocrinology, with Dr. Roy Hertz, Dr. Delbert M .
Bergenstal, Dr . Mortimer Lipseu, and others was a
strong but independent component .
The intramural branches were descendants of the
original NCI structure and still considered themselves
the real National Cancer Institute . They reported to the
NIH Associate Director, a post inherited by Mider from
Dr . Joseph E . Smadel, and were jealous of their
prerogatives . But by 1960 it was obvious that NCI and,
indeed, all of NIH, was a national activity not circumscribed by the Bethesda contingent .
OTHER CANCER CENTERS
In the early 1960's, the leading centers in cancer
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research in the United States were easily identifiable .

The Memorial HospitalSloanKettering combine in
New York City, with Heller trying to ride herd and Dr .
Frank Horsfall orienting the scientific approaches
along virology, were in the front ranks as usual . The
attempted monopoly of chemotherapy by Rhoads was
long gone, but Burchenal was an active and effective
participant in the national program .
Next in size if not in prestige were the Roswell Park
Memorial Institute in Buffalo, remade by Dr . George
Moore, and the M . D . Anderson Hospital and Tumor
Clinic in Houston, the monarchy of Dr . R . Lee Clark .
Both centers had extensive chemotherapy programs and
were headquarters for study groups. The computer
services for such grottps were evolved primarily by Dr .
Abraham Lilienfeld in Buffalo and by Dr . Wilfrid J .
Dixon in Los Angeles . Development of large amounts
of tumor cells and their fractions became a preoccupation of Roswell Park, and Dr . Theodore S . Hauschka
emphasized the study of chromosome aberrations in
cancer and other diseases . At the Houston center, Dr.
Leon Dmochowski was a pioneer in applying electron
microscopy to tumor virology, and the first induction
of sarcomas in hamsters with adenovirus was reported
by Dr . John J . Trentin (95) .
The McArdle Laboratory for Cancer Research at the
University of Wisconsin in Madison continued to be
the leader in the biochemical aspects of carcinogenesis .
Under the easy rule of Dr . Harold P . Rusch, the talents
of Drs . James A . and Elizabeth C. Miller led to the
elucidation of the metabolic conversions of the azo dye
carcinogens, and Dr . Charles Heidelberger explored
mechanisms in organ cultures and was inventing 5fluorouracil . The clinical area, separate from the laboratory, was developed by Dr. Anthony R . Curreri and
Dr . Fred J . Ansfield (96) . Training of carcinogenesis
biochemists and cancer chemotherapists were important activities at the Wisconsin center .
All other cancer research centers were smaller or less
prominent . Huggins held his penchant for smallness at
the Ben May Laboratory at the University of Chicago,
established especially for him . Dr . Harry Shay was in
charge of the Fels Research Institute at Temple Uni
versity, in Philadelphia, where he explored the induction of breast cancer in rats fed Smethylcholanthrene .
The Lankenau Hospital Tumor Institute, founded by
Dr. Stanley Reimann, was expanding in a new location
at Fox Chase in Philadelphia . Dr . B . J . Kennedy at
University Hospital in Minneapolis was spearheading
the development of oncology as a clinical specialty .
Internationally, by 1960 the United States program
in cancer had no close competitors . The European
centers were now rehabilitated from the effects of
World War 11 . In London, the Chester Beatty Cancer
Research Institute under Dr . Alexander Haddow was in
the forefront of carcinogenesis research, and the Imperial Cancer Research Fund laboratories were engaged
in endocrine research . In Sweden, Drs . George and Eva
Klein at the Karolinska Institutet were leaders in the
nascent field of tumor immunology . Dr . Johannes
Clemmesen continued his cancer epidemiologic studies

In the Middie : NCI, 1954-63 1313

in Denmark . Japan's Drs . T . 1'oshida and W . Naka
tiara tcstnncd their important positions, and the Japanese pharmaceutical industry became involved in cancer chemotherapy . Dr . Mitsuo Segi at Tohuku University in Sendai was contributing to cancer epidemiology. The Russians, with a national cancer program
of their own, under Dr . Nikolai Blokhin of the U .S .S .R .
Academy of Medical Sciences in Moscow were closely
patterning their activities to those of the United States,
a development that eventually led to collaborative
projects agreed upon by diplomatic treaties . The German Cancer Research Center in Heidelberg, the French
]nstitute of Scientific Cancer Research at Villejuif, and
the Italian National Cancer Institute in Milan also
were adding their talents to cancer research .
AMERICAN CANCER SOCIETY

The ACS, as usual, balanced the NCI, serving as its

spearhead before Congressional committees as well as
its critic . The Society had a stable board of directors
who were self-perpetuating conservative leaders in
medicine and commerce . The staff, whose functions
were quite different than those of the NCI staff, was
headed by an ex-banker, Mr . Lane Adams . The main
function of the ACS was to raise money for its
activities, and this function was particularly impressed
on its state organizations . One-half of the monies
raised from the public was sent to the New York
headquarters, where one-third was allocated nationally
for research .
The ACS did not conduct its own research except in
the field of epidemiology, headed by Dr . C . Cuyler
Hammond . His work on smoking and lung cancer was
extended to collaboration with Dr . Oscar Auerbach (97)
on biometrically selected sections of the lung and on
the induction of lung cancer in dogs that were taught
to smoke through tracheostomies (98) . These endeavors
were rebutted by the tobacco industry, which made
ACS relations somewhat difficult in the tobacco-growing states . Under the lung cancer committee, an
evaluation was done on radiologic and cytologic
screening for early detection, which proved negative
(99) .
Opposition to the ACS did develop, primarily about
the conduct of its annual drive for funds . In Michigan,
the ACS rejected a plan to become part of one annual
drive, which was more convenient for the automobile
moguls than were interruptive individual drives . The
Michigan Cancer Society was formed and remained
separate from the ACS . The Leukemia Society of
America represented another competing group that
remained independent despite efforts at amalgamation .
But ovcrall, the ACS remained one of the foremost
voluntary health agencies in the United States, with a
proud record of achievement in support of research and
professional and public education .
' The ACS considered public and professional education among its main goals and coordinated its State
and local branches effectively . Coordination was facilitated by keeping the authority for brochures and other

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printed material firmly at the central headquarters .

Professional meetings were usually orgnnized and supportcd jointly with NCI, with agterment that ACS
have the more visible position for public relations
purposes .
After 11 years of advice by the COG of the National
Research Council on the research allocations for ACS
funds, this relationship was terminated by Dr . Harry
Weaver . He had been hired from the National Foundation Against Infantile Paralysis, where he had engineered the activities that led to the successful de
velopment of the killed-type vaccine by Dr . Jonas Salk .
The ACS also wanted to try more directed, targetoriented research, and the first step was a disengage_ ment from COG . The disengagement in 1956 was
traumatic and full of dire forebodings, but its effectsother than in administration-were hard to define .
The same scientists and clinicians were appointed to a
different set of panels, and reviewed similar proposals
under similar conditions but involving ever-greater
budgets . However, it was easier to organize study
groups and support them for specific goals, such as the
evaluation of sputum cytology and chest X-rays in the
diagnosis of lung cancer . The executive secretary of
COG, Dr. O . Malcolm Ray, became deputy to Meader
at NCI-another example of the close interlinks of
ACS and NCI . There were, and are, serious drawbacks
from such an intimate, cozy relationship . More than
one example exists of investigators who became "unacceptable" to one of the organizations and found it
virtually impossible to be in the good graces of the
other. There is something to be said for limited
coordination in research .
The relationships between ACS, NCI, and American
Association for Cancer Research (AACR) were interesting to observe . Officially, there was close camaraderie
and comity of objectives . And this was the case at the
highest echelons, the Directors . At the lower levels of
working arrangements, the relationships would best be
described as wary and covertly competitive . To the NCI
professionals, the voluntary agency staff appeared to be
too public-relations oriented . The ACS staff, receiving
salaries higher than those afforded by the Government,
looked down from New York at the dowdy un .aorldly
scientists . The AACR, the bastion of cancer researchers,
after several attempts to organize joint programs along
scientific lines, gave up attempts to do so with ACS .
During the late 1960's, when the clinical cancer so
cieties began to proliferate, ACS stepped forward to
coordinate them under a Federation of Clinical OncoIogic Societies . This was looked upon with suspicion
by AACR, which decided to exclude itself from the
arrangement . There the stresses between clinicians and
laboratory workers added to the lack of understanding .
In the complicated social structure represented by the
democracy of the United States, a variety of organizations and interests are better than monopolistic conglomerates. As a voluntary public agency, ACS has and
will continue to have an essential voice in the cancer
affairs of the nation . It will continue to represent the
citizens' lobby group without which NCI would find it
JNCI . VOL . 62 . NO. 5, MAl' 1979

314 Shlmktn

Flara[ 5 .-Audiencc at ihe Fourth National Cancer c :nnference, jointly sponsored by ACS and NCI and held September 13-15, 196Q in Afim
neapolis, Minnesota . The conference was attended by over 1,600 physicians, research scientists, and c :mcer specialists from the United Siates
and Europe .

J\CI . VOL . 69, NO . 5 . MAY 1979

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In the Middle: NCI, 1954-63 1315

hard to expand, if not lo exist . The role for each is

arrised at by trial and error, by the very human push
and tug between individual and institutional interests .
THE CHAPTER CLOSES
The new organization of NCI was unfolded at the
Fourth National Cancer Conference, held in Minneapolis in 1960 . 1 was the co-chairman for this conference and was asked to deliver the keynote address (100) .
A year later, preparations were afoot for an exhibit,
"Man Against Cancer," that was opened in 1962 in
Washington to commemorate the 25th anniversary of
NCI and to inaugurate Cancer Progress Year . Mr .
James Rieley, information officer for NCI, enlisted my
services . Even bigger things were afoot for cancer and
heart disease, starting with a President's Conference in
1961 and emerging as the President's Commission on
Heart Disease, Cancer, and Stroke .
The 3 years I spent in the Field Studies Area were
busy, happy, and productive . One unremedied aspect
was the lack of real working relationships with other
areas of NCI . I recall not a single staff meeting in
which all the Associate Directors were briefed by the
Director or at which discussion was held about the
research approaches to cancer . An Associate Director
for Programs was appointed in 1961, but I recall no
input or output to or from me during my tenure .
In 1963 1 requested and was granted retirement from
the Public Health Service . I felt that it was time to
make a move, to try something else while I was still in
my early fifties . Also, I could double my salary by
taking one of several offers that came my way once I
identified myself as available . I elected to join Temple
University in Philadelphia, where the vice president for
health sciences was Dr . Leroy E . Burney . It had an area
for cancer research, the Fels Research Institute, which
included Dr. Sidney Weinhouse, another man whom I
admired . I '
Once again my family was relocated and I undertook
another variant to my preoccupation with cancer .
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~
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a
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